Glutathione reductase is inhibited by acetaminophen-glutathione conjugate in vitro
The aim of the present work was to investigate a new mechanism likely contributing to the toxic action of acetaminophen, especially to explore the possible inhibition of glutathione reductase through an acetaminophen-glutathione conjugate (APAP-SG). APAP-SG conjugate was synthesized by organic synth...
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| Veröffentlicht in: | Physiological research 2010-01, Vol.59 (2), p.225-232 |
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| creator | Rousar, T Pařík, P Kucera, O Bartos, M Červinková, Z |
| description | The aim of the present work was to investigate a new mechanism likely contributing to the toxic action of acetaminophen, especially to explore the possible inhibition of glutathione reductase through an acetaminophen-glutathione conjugate (APAP-SG). APAP-SG conjugate was synthesized by organic synthesis and purified by column chromatography. The inhibitory effect of the conjugate on two types of glutathione reductase (from yeasts and rat hepatocytes) was tested spectro-photometrically. We found that the enzyme activity was reduced similarly after the treatment with 2.96 mM acetaminophen-glutathione conjugate in both yeast and hepatocyte glutathione reductases (GR); the enzyme activity was inhibited to 52.7+/-1.5 % (2.4+/-0.3 mU/ml) in yeast GR (control activity was 5.6+/-0.3 mU/ml) and to 48.1+/-8.8 % (2.2+/-0.2 mU/ml) in rat hepatocytes lysate GR (control activity was 5.2+/-0.2 mU/ml). In addition, the enzyme activity (from hepatocytes lysate) was decreased to 79+/-7 %, 67+/-2 % and 39+/-7 %, in 0.37, 1.48 and 3.7 mM concentration of the conjugate, respectively. We found that glutathione reductase, the essential enzyme of the antioxidant system, was dose-dependently inhibited by the product of acetaminophen metabolism - the conjugate of acetaminophen and glutathione. |
| doi_str_mv | 10.33549/physiolres.931744 |
| format | Article |
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APAP-SG conjugate was synthesized by organic synthesis and purified by column chromatography. The inhibitory effect of the conjugate on two types of glutathione reductase (from yeasts and rat hepatocytes) was tested spectro-photometrically. We found that the enzyme activity was reduced similarly after the treatment with 2.96 mM acetaminophen-glutathione conjugate in both yeast and hepatocyte glutathione reductases (GR); the enzyme activity was inhibited to 52.7+/-1.5 % (2.4+/-0.3 mU/ml) in yeast GR (control activity was 5.6+/-0.3 mU/ml) and to 48.1+/-8.8 % (2.2+/-0.2 mU/ml) in rat hepatocytes lysate GR (control activity was 5.2+/-0.2 mU/ml). In addition, the enzyme activity (from hepatocytes lysate) was decreased to 79+/-7 %, 67+/-2 % and 39+/-7 %, in 0.37, 1.48 and 3.7 mM concentration of the conjugate, respectively. We found that glutathione reductase, the essential enzyme of the antioxidant system, was dose-dependently inhibited by the product of acetaminophen metabolism - the conjugate of acetaminophen and glutathione.</description><identifier>ISSN: 0862-8408</identifier><identifier>EISSN: 1802-9973</identifier><identifier>DOI: 10.33549/physiolres.931744</identifier><identifier>PMID: 19537930</identifier><language>eng</language><publisher>Czech Republic: Institute of Physiology</publisher><subject>Acetaminophen - chemical synthesis ; Acetaminophen - toxicity ; Analgesics, Non-Narcotic - chemical synthesis ; Analgesics, Non-Narcotic - toxicity ; Animals ; Apoptosis ; Cells, Cultured ; Dose-Response Relationship, Drug ; Drug Combinations ; Enzyme Activation - drug effects ; Glutathione - chemical synthesis ; Glutathione - toxicity ; Glutathione Reductase - antagonists & inhibitors ; Glutathione Reductase - metabolism ; Hepatocytes - drug effects ; Hepatocytes - enzymology ; Hepatocytes - pathology ; In Vitro Techniques ; Liver ; Male ; Metabolites ; Rats ; Rats, Wistar ; Rodents ; Toxicity</subject><ispartof>Physiological research, 2010-01, Vol.59 (2), p.225-232</ispartof><rights>Copyright Institute of Physiology 2010</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c398t-af5ec69fdfe1314b40d4223dfc106fd95633f4d7a3af6491297f3b6ed7e101063</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,864,27922,27923</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19537930$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Rousar, T</creatorcontrib><creatorcontrib>Pařík, P</creatorcontrib><creatorcontrib>Kucera, O</creatorcontrib><creatorcontrib>Bartos, M</creatorcontrib><creatorcontrib>Červinková, Z</creatorcontrib><title>Glutathione reductase is inhibited by acetaminophen-glutathione conjugate in vitro</title><title>Physiological research</title><addtitle>Physiol Res</addtitle><description>The aim of the present work was to investigate a new mechanism likely contributing to the toxic action of acetaminophen, especially to explore the possible inhibition of glutathione reductase through an acetaminophen-glutathione conjugate (APAP-SG). APAP-SG conjugate was synthesized by organic synthesis and purified by column chromatography. The inhibitory effect of the conjugate on two types of glutathione reductase (from yeasts and rat hepatocytes) was tested spectro-photometrically. We found that the enzyme activity was reduced similarly after the treatment with 2.96 mM acetaminophen-glutathione conjugate in both yeast and hepatocyte glutathione reductases (GR); the enzyme activity was inhibited to 52.7+/-1.5 % (2.4+/-0.3 mU/ml) in yeast GR (control activity was 5.6+/-0.3 mU/ml) and to 48.1+/-8.8 % (2.2+/-0.2 mU/ml) in rat hepatocytes lysate GR (control activity was 5.2+/-0.2 mU/ml). In addition, the enzyme activity (from hepatocytes lysate) was decreased to 79+/-7 %, 67+/-2 % and 39+/-7 %, in 0.37, 1.48 and 3.7 mM concentration of the conjugate, respectively. We found that glutathione reductase, the essential enzyme of the antioxidant system, was dose-dependently inhibited by the product of acetaminophen metabolism - the conjugate of acetaminophen and glutathione.</description><subject>Acetaminophen - chemical synthesis</subject><subject>Acetaminophen - toxicity</subject><subject>Analgesics, Non-Narcotic - chemical synthesis</subject><subject>Analgesics, Non-Narcotic - toxicity</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Cells, Cultured</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Combinations</subject><subject>Enzyme Activation - drug effects</subject><subject>Glutathione - chemical synthesis</subject><subject>Glutathione - toxicity</subject><subject>Glutathione Reductase - antagonists & inhibitors</subject><subject>Glutathione Reductase - metabolism</subject><subject>Hepatocytes - drug effects</subject><subject>Hepatocytes - enzymology</subject><subject>Hepatocytes - pathology</subject><subject>In Vitro Techniques</subject><subject>Liver</subject><subject>Male</subject><subject>Metabolites</subject><subject>Rats</subject><subject>Rats, Wistar</subject><subject>Rodents</subject><subject>Toxicity</subject><issn>0862-8408</issn><issn>1802-9973</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNpNkFFLwzAURoMobk7_gA9SfK8muWnTPMrQKQwE0eeSNjdrxtbMJBX27y1uMJ_uyznfhUPILaMPAIVQj7tuH53fBIwPCpgU4oxMWUV5rpSEczKlVcnzStBqQq5iXFPKJZVwSSZMFSAV0Cn5WGyGpFPnfI9ZQDO0SUfMXMxc37nGJTRZs890i0lvXe93Hfb56p_T-n49rHQanT77cSn4a3Jh9SbizfHOyNfL8-f8NV--L97mT8u8BVWlXNsC21JZY5EBE42gRnAOxraMltaoogSwwkgN2pZCMa6khaZEI5HREYEZuT_s7oL_HjCmeu2H0I8v64LLCkoJxQjxA9QGH2NAW--C2-qwrxmt_yrWp4r1oeIo3R2Xh2aL5qQcs8Ev9C1yVQ</recordid><startdate>20100101</startdate><enddate>20100101</enddate><creator>Rousar, T</creator><creator>Pařík, P</creator><creator>Kucera, O</creator><creator>Bartos, M</creator><creator>Červinková, Z</creator><general>Institute of Physiology</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>4T-</scope><scope>4U-</scope><scope>7RV</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>BYOGL</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB0</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>M7P</scope><scope>MBDVC</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope></search><sort><creationdate>20100101</creationdate><title>Glutathione reductase is inhibited by acetaminophen-glutathione conjugate in vitro</title><author>Rousar, T ; Pařík, P ; Kucera, O ; Bartos, M ; Červinková, Z</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c398t-af5ec69fdfe1314b40d4223dfc106fd95633f4d7a3af6491297f3b6ed7e101063</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Acetaminophen - chemical synthesis</topic><topic>Acetaminophen - toxicity</topic><topic>Analgesics, Non-Narcotic - chemical synthesis</topic><topic>Analgesics, Non-Narcotic - toxicity</topic><topic>Animals</topic><topic>Apoptosis</topic><topic>Cells, Cultured</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug Combinations</topic><topic>Enzyme Activation - drug effects</topic><topic>Glutathione - chemical synthesis</topic><topic>Glutathione - toxicity</topic><topic>Glutathione Reductase - antagonists & inhibitors</topic><topic>Glutathione Reductase - metabolism</topic><topic>Hepatocytes - drug effects</topic><topic>Hepatocytes - enzymology</topic><topic>Hepatocytes - pathology</topic><topic>In Vitro Techniques</topic><topic>Liver</topic><topic>Male</topic><topic>Metabolites</topic><topic>Rats</topic><topic>Rats, Wistar</topic><topic>Rodents</topic><topic>Toxicity</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Rousar, T</creatorcontrib><creatorcontrib>Pařík, P</creatorcontrib><creatorcontrib>Kucera, O</creatorcontrib><creatorcontrib>Bartos, M</creatorcontrib><creatorcontrib>Červinková, Z</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Docstoc</collection><collection>University Readers</collection><collection>Nursing & Allied Health Database</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>East Europe, Central Europe Database</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Research Library</collection><collection>Biological Science Database</collection><collection>Research Library (Corporate)</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><jtitle>Physiological research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Rousar, T</au><au>Pařík, P</au><au>Kucera, O</au><au>Bartos, M</au><au>Červinková, Z</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Glutathione reductase is inhibited by acetaminophen-glutathione conjugate in vitro</atitle><jtitle>Physiological research</jtitle><addtitle>Physiol Res</addtitle><date>2010-01-01</date><risdate>2010</risdate><volume>59</volume><issue>2</issue><spage>225</spage><epage>232</epage><pages>225-232</pages><issn>0862-8408</issn><eissn>1802-9973</eissn><abstract>The aim of the present work was to investigate a new mechanism likely contributing to the toxic action of acetaminophen, especially to explore the possible inhibition of glutathione reductase through an acetaminophen-glutathione conjugate (APAP-SG). APAP-SG conjugate was synthesized by organic synthesis and purified by column chromatography. The inhibitory effect of the conjugate on two types of glutathione reductase (from yeasts and rat hepatocytes) was tested spectro-photometrically. We found that the enzyme activity was reduced similarly after the treatment with 2.96 mM acetaminophen-glutathione conjugate in both yeast and hepatocyte glutathione reductases (GR); the enzyme activity was inhibited to 52.7+/-1.5 % (2.4+/-0.3 mU/ml) in yeast GR (control activity was 5.6+/-0.3 mU/ml) and to 48.1+/-8.8 % (2.2+/-0.2 mU/ml) in rat hepatocytes lysate GR (control activity was 5.2+/-0.2 mU/ml). In addition, the enzyme activity (from hepatocytes lysate) was decreased to 79+/-7 %, 67+/-2 % and 39+/-7 %, in 0.37, 1.48 and 3.7 mM concentration of the conjugate, respectively. We found that glutathione reductase, the essential enzyme of the antioxidant system, was dose-dependently inhibited by the product of acetaminophen metabolism - the conjugate of acetaminophen and glutathione.</abstract><cop>Czech Republic</cop><pub>Institute of Physiology</pub><pmid>19537930</pmid><doi>10.33549/physiolres.931744</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Physiological research, 2010-01, Vol.59 (2), p.225-232 |
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| subjects | Acetaminophen - chemical synthesis Acetaminophen - toxicity Analgesics, Non-Narcotic - chemical synthesis Analgesics, Non-Narcotic - toxicity Animals Apoptosis Cells, Cultured Dose-Response Relationship, Drug Drug Combinations Enzyme Activation - drug effects Glutathione - chemical synthesis Glutathione - toxicity Glutathione Reductase - antagonists & inhibitors Glutathione Reductase - metabolism Hepatocytes - drug effects Hepatocytes - enzymology Hepatocytes - pathology In Vitro Techniques Liver Male Metabolites Rats Rats, Wistar Rodents Toxicity |
| title | Glutathione reductase is inhibited by acetaminophen-glutathione conjugate in vitro |
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